The term avermectin (previously referred to as C-076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The avermectin compounds are a series of macrolides, each of which is substituted thereon at the 13-position with a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity.
Also included in the prior art are certain synthetically modified avermectins such as 22,23-dihydro avermectin B1a/B1b also known as ivermectin.
The avermectin series of compounds, which are isolated from a fermentation broth, have the following structure: ##STR1## wherein R is the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and PA1 R.sub.3 is methoxy or hydroxy. PA1 R.sub.1 is hydrogen of hydroxy provided that R.sub.1 is present only when the broken line at the 22,23-position incicates a single bond; PA1 R.sub.2 is methyl, ethyl, iso-propyl or sec-butyl; PA1 R.sub.3 is hydroxy or methoxy; PA1 R.sub.4 is hydrogen, hydroxy, ##STR4## R.sub.5 is hydroxy, keto or --NR.sub.6 R.sub.7 and R.sub.6 and R.sub.7 are independently hydrogen, loweralkyl, loweralkanoyl, loweralkylsulfonyl or substituted benzene sulfonyl, wherein the substituent is halogen. PA1 Ph is phenyl and Y is halogen. The reduction procedure is completely described in U.S. Pat. No. 4,199,569 to Chabala et al.
There are eight different major avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a Double Bond sec-butyl --OCH.sub.3 A1b Double Bond iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2B --OH iso-propyl --OCH.sub.3 B1a Double Bond sec-butyl --OH B1b Double Bond iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
The milbemycin compounds, which have a methyl or ethyl group at the 25-position and lack the 13-disaccharide group are also starting materials for the instant compounds. They are disclosed in U.S. Pat. No. 3,950,360.